Diabetes mellitus is a disease of major global importance, increasing in frequency at almost epidemic rates, such that the worldwide prevalence in 2006 is 170 million people and predicted to at least double over the next 10-15 years. Diabetes is characterized by a chronically raised blood glucose concentration (hyperglycemia), due to a relative or absolute lack of the pancreatic hormone, insulin. Within the healthy pancreas, beta cells, located in the islets of Langerhans, continuously produce and secrete insulin according to the blood glucose levels, maintaining near constant glucose levels in the body.
Much of the burden of the disease to the user and to health care resources is due to the long-term tissue complications, which affect both the small blood vessels (microangiopathy, causing eye, kidney and nerve damage) and the large blood vessels (causing accelerated atherosclerosis, with increased rates of coronary heart disease, peripheral vascular disease and stroke). The Diabetes Control and Complications Trial (DCCT) demonstrated that development and progression of the chronic complications of diabetes are greatly related to the degree of altered glycemia as quantified by determinations of glycohemoglobin (HbA1c). [DCCT Trial, N Engl J Med 1993; 329: 977-986, UKPDS Trial, Lancet 1998; 352: 837-853. BMJ 1998; 317, (7160): 703-13 and the EDIC Trial, N Engl J Med 2005; 353, (25): 2643-53].Thus, maintaining normoglycemia by adequate insulin delivery can be of utmost importance.
Insulin infusion device can deliver rapid acting insulin (e.g. Lispro, Aspart, etc.) 24 hours a day through a cannula placed under the skin. Rapid acting insulin effect begins in about 10 minutes after administration, peaks at 1 to 1.5 hours after administration, and ends in about two to six hours after the administration. The duration of insulin action (DIA) is variable and thus this parameter can be set (programmed) in the pump by the user and/or caregiver.
A skin-securable insulin infusion device was disclosed in co-owned, U.S. patent application Ser. No. 11/397,115 (published as US2007/0106218) and International Patent Application No. PCT/IL06/001276 (published as WO2007/052277), and International Patent Application No. PCT/IL09/000388 (published as WO2009/125398) claiming priority to U.S. Provisional Patent Application No. 61/123,509, the disclosures of which are incorporated herein by reference in their entireties.
Insulin infusion device can be integrated with a continuous glucose monitor allowing open and closed loop systems (patient boluses at meals and automatic administration respectively). Such device integrating insulin delivery and glucose monitoring was disclosed in co-owned, U.S. patent application Ser. No. 11/706,606 (published as US2007/0191702) and International Patent Application No. PCT/IL07/000163 (published as WO2007/093981), co-owned, U.S. patent application Ser. No. 11/963,481 (published as US2008/0214916) and International Patent Application No. PCT/IL07/001579 (published as WO2008/078319), and co-owned International Patent Application No. PCT/IL08/001521 (published as the disclosures of which are incorporated herein by reference in their entireties.
One of the major advantages of insulin pumps is the convenience of insulin bolus administration at any desired time. However, the effect of boluses may overlap, hence the amount of active insulin that is still “working” in the body (hereinafter “residual insulin” or “RI”) from previous boluses should be taken into account. Accumulation of insulin in the body, or “insulin stacking”, may lead to life-threatening hypoglycemia. Prevention of hypoglycemia can be especially important (but not limited) at bedtime since users are typically unaware of nocturnal hypoglycemia.
A simple rule can be applied to calculate the RI. It is often stated that after bolus administration 20% of a dose is absorbed each hour, so that after 5 hours there is no active insulin remaining in the body. For example, FIG. 1 shows the insulin consumption according to the described rule (adapted from Using Insulin © 2003). Knowing the RI, can assist in providing the desired bolus dose. For example, if a 5 U bolus is planned 2 hours after a 6 U bolus [RI=6 U×0.2×2=3.6 U) the actual administered bolus should be only 1.4 U (5 U−3.6 U=1.4 U).
Most bolus recommendation tools, provided by different insulin pumps, can take the RI parameter into account. The recommended amount of insulin in the bolus to be delivered can be established, for example, by calculations, as described in U.S. Pat. Ser. No. 6,936,029 assigned to Medtronic MiniMed, or it can be selected by a method for selection of the desired bolus dose, as described in co-owned, International Application No. PCT/IL2008/000380 (published as WO2008/114254) and U.S. patent application Ser. No. 12/051,400 (published as 2008/0234663), the disclosures of which are incorporated herein by reference in their entireties. Some pumps (e.g., Deltec's, Insulet's) use linear plots to predict the residual insulin, while other pumps (e.g., Animas', MiniMed's) use curvilinear plots which better approximate the pharmacokinetics actions of insulin (Diabetes Technology and Therapeutics, 2008, 10(6), p. 441-44).
Most available bolus calculators take into account RI from boluses which have been administered during a time interval prior to a current bolus administration. Typically, this time interval does not exceed above the DIA, and the accumulated RI is subtracted from the current bolus dose to be delivered. Although insulin stacking can be prevented, this simple calculation of RI may lead to under-dosing if previous boluses administration times are very close to the current bolus administration time. For example, when a pump user eats a main course, he/she will first have to administer a bolus to balance the main course's carbohydrates. If the user further eats a desert 10 minutes after completing the main course, the pump and/or bolus calculator may indicate a high RI (resulted from the bolus administered prior to the main course to cover the main course) and may not require an additional bolus to cover the carbohydrates of the desert. Such indication can be misleading because the high RI may be sufficient to offset merely the main course but insufficient to offset the desert. The outcome of this miscalculation can lead to unbalanced offset of carbohydrates and subsequent hyperglycemia.